Back to EveryPatent.com
United States Patent |
5,077,048
|
Kimura
,   et al.
|
December 31, 1991
|
Bowel lavage composition
Abstract
A bowel lavage composition which comprises one or more of a water-soluble
polymer selected from the group consisting of polyethylene glycol,
dextran, dextrin, hydroxyethylated starch, polydextrose, arabic gum,
pullulan and pectin; a sodium salt of an organic; a potassium salt of an
organic acid; sodium chloride; potassium chloride and sodium sulfate,
having the following formulation:
______________________________________
Water-soluble polymer 10-150 g
Sodium salt of an organic acid
5-60 mmol
Potassium salt of an organic acid
0-12 mmol
Sodium chloride 7-60 mmol
Potassium chloride 0-12 mmol
Sodium sulfate 0-20 mmol
______________________________________
wherein total potassium ion content in said composition ranges from 2 to 12
mEq. The bowel lavage composition is easily prepared in the form of the
lavage solution when used, which is easily taken by patients, has reduced
absorption of water, does not exert influence upon the electrolyte balance
in living body with an excellent cleansing effect, does not contain
hydrogen carbonate ion, and hence, is pharmaceutically stable and can be
stored for a long period of time.
Inventors:
|
Kimura; Isami (Shiga, JP);
Kamiya; Akemi (Shiga, JP);
Shiraishi; Sumihiro (Otsu, JP);
Sato; Makoto (Moriyama, JP)
|
Assignee:
|
Morishita Pharmaceutical Co., Ltd. (Osaka, JP)
|
Appl. No.:
|
464522 |
Filed:
|
January 12, 1990 |
Current U.S. Class: |
424/422; 424/400; 424/439; 514/892 |
Intern'l Class: |
A61K 009/08 |
Field of Search: |
424/422,400,439
514/892
|
References Cited
U.S. Patent Documents
3211614 | Oct., 1965 | Embring et al. | 167/56.
|
3495010 | Feb., 1970 | Fossel et al. | 514/547.
|
Foreign Patent Documents |
87/00754 | Feb., 1987 | WO.
| |
Other References
J. Hewitt et al., "Whole-Gut Irrigation in Preparation for Large-Bowel
Surgery", The Lancet, vol. 2, (1973), pp. 337-340.
Marc-Andre Bigard et al., "Fatal Colonic Explosion During Colonoscopic
Polypectomy", Gastroenterology, vol. 77 (1979) pp. 1307-1310.
G. R. Davis et al., "Development of a Lavage Solution Associated with
Minimal Water and Electrolyte Absorption or Secretion", Gastroenterology,
vol. 78 (1980), pp. 991-995.
Int'l. Advances in Surg. Oncology, 6:257-270 (1983), Keighley et al.,
"Indications and Techniques for Bowell Preparation in Colorectal Cancer".
Gastroenterology, vol. 78, No. 5, May 1980, Davis et al., "Development of a
Lavage Solution Associated with Minimal Water and Electrolyte Absorption
or Secretion".
|
Primary Examiner: Page; Thurman K.
Assistant Examiner: Spear; James M.
Attorney, Agent or Firm: Wegner, Cantor, Mueller & Player
Claims
What is claimed is:
1. A bowel lavage composition which comprises at least one water-soluble
polymer selected from the group consisting of polyethylene glycol,
dextran, dextrin, hydroxyethylated starch, polydextrose, arabic gum,
pullulan and pectin, present in the amount of 10-150g; a sodium salt of an
organic acid, present in the amount of 5-60 mmol; sodium chloride, present
in the amount of 7- 60 mmol; and at least one member selected from the
group consisting of a potassium salt of an organic acid and potassium
chloride, the total potassium ion content of the composition being from
2-12 mEq; wherein the organic acid is selected from the group consisting
of acetic acid, lactic acid, citric acid, succinic acid, malic acid and
tartaric acid the composition being free of hydrogen carbonate ions.
2. The composition of claim 1 which is dissolved in water.
3. The composition of claim 1, wherein the organic acid is a member of the
class consisting of citric acid, succinic acid, malic acid and tartaric
acid.
4. The composition of claim 1, wherein the organic acid is citric acid.
5. The composition according to claim 1, further comprising sodium sulfate
in an amount of up to 20 mmol.
6. The composition of claim 2, wherein the amount of water is from 1-4
liters.
Description
The present invention relates to a bowel lavage composition which is used
by dissolving in water.
PRIOR ART
Bowel cleansing is extremely important prior to accurate diagnosis in
colonoscopy or double-contrast barium enema examination and for preventing
infection after surgery of a lower intestine.
For such bowel cleansing, there has hitherto been employed a modified Brown
method, which comprises administering a cathartic after dietary
restriction with a low-residue diet or a liquid diet for several days and
conducting a high enema with a large amount of warm water just before
examination or surgery to cleanse the interior of colon. However, this
method is time-consuming, painful for patients, and exerts a bad influence
upon the electrolyte balance of body fluid and nutritional status.
It has been proposed a method comprising rapid ingestion of a large volume
of a saline-based electrolyte solution and this method has been reported
to be effective for pretreatment for colonoscopy [J. Hewitt et al.,
Lancet, 2, 337 (1973)].
However, this method is also painful for patients since patients must take
a large volume of the electrolyte solution as much as 7 to 12 liters and
further causes an absorption of a fairly large amount of sodium ion,
chloride ion and water, and hence, this method cannot be applied to the
patients with renal disease who are incapable of excreting salts or water
or to the aged patients.
Thereafter, a balanced electrolyte solution (hereinafter referred to as
"BES") comprising sodium chloride, potassium chloride and sodium hydrogen
carbonate has been proposed in order to keep normal electrolyte balance in
the living body. Although this BES does not affect the electrolyte balance
in the living body so much, it is accompanied with an absorption of a
fairly large volume of water.
In order to reduce such an absorption of water, an electrolyte composition
supplemented with mannitol as an osmotically active agent has been
proposed and confirmed to be effective. However, it is reported that
mannitol in the composition is degraded by colonic bacteria to generate
hydrogen gas and thereby an explosion accident in the large intestine was
observed during polypectomy of the large intestine [M.A. Bigard et al
Gastroenterology, 77, 1307 (1979)].
Davis et al. have proposed an electrolyte composition employing poorly
absorbable polyethylene glycol in place of mannitol as an osmotically
active agent. They have further proposed a unique electrolyte composition
(commercially available as "Golytely") where a part of sodium chloride in
the electrolyte composition is replaced with sodium sulfate in order to
inhibit an absorption of sodium ion and confirmed to be useful [G.R. Davis
et al., Gastroenterology, 78, 991 (1980)].
However, this Golytely has a bitter taste due to a large amount of sodium
sulfate contained therein, and hence, it is not suitable for use in such a
large amount as for intestinal washing.
Another unique electrolyte composition has been proposed which is prepared
by removing sodium sulfate from the Golytely electrolyte composition,
instead increasing the amount of polyethylene glycol and adjusting the
osmotic pressure to isotonic (WO 87/00754).
It has been described in said literature that this lavage solution has less
bitter taste and reduced absorption of water and electrolyte ions.
However, when compared with Golytely, the lavage solution gives a clammy
feeling when used due to higher concentration of polyethylene glycol and
it is expected that sodium ion in the living body is excreted since the
lavage solution contains lower concentration of sodium ion, which exerts a
bad influence upon the electrolyte balance in the living body. The lavage
solution is further disadvantageous in that it is pharmaceutically
instable due to hydrogen carbonate ion contained therein and hence
required for preparation when used and there is required much time to
dissolve a large amount of polyethylene glycol.
SUMMARY OF THE INVENTION
In order to solve the above-mentioned problems, the present inventors have
firstly studied the action, effect and necessity of each component used in
the conventional bowel lavage composition in dogs and rats and then have
intensively studied as to use of other components which have hitherto
never been used for a bowel lavage composition.
As a result, it has been found that the blood pH is apparently affected by
the hydrogen carbonate ion level in the bowel lavage composition, that the
blood pH is never affected by an organic acid ion when it is used in place
of the hydrogen carbonate ion, that a potassium ion level which does not
affect the electrolyte balance in the living body is preferably in such a
small range as 2 to 12 mEq/liter, that a chloride ion level is preferably
in the range of from 7 to 60 mEq/liter, and that it is preferable to
adjust the osmotic pressure of the aqueous solution to the preferred range
of from 270 to 350 mOsm with sodium ion, an organic acid ion and a
water-soluble polymer.
The object of the present invention is to provide a bowel lavage
composition which can easily be taken by patients, shows reduced
absorption of water, does not exert a bad influence upon the electrolyte
balance in the living body and shows an excellent cleansing effect.
The present invention concerns a bowel lavage composition which comprises
one or more of a water-soluble polymer selected from the group consisting
of polyethylene glycol, dextran, dextrin, hydroxyethylated starch,
polydextrose, arabic gum, pullulan and pectin; a sodium salt of an organic
acid; a potassium salt of an organic acid; sodium chloride; potassium
chloride and sodium sulfate, having the following formulation:
______________________________________
Water-soluble polymer 10-150 g
Sodium salt of an organic acid
5-60 mmol
Potassium salt of an organic acid
0-12 mmol
Sodium chloride 7-60 mmol
Potassium chloride 0-12 mmol
Sodium sulfate 0-20 mmol
______________________________________
wherein total potassium ion content in said composition ranges from 2 to 12
mEq.
The most preferable water-soluble polymer is polyethylene glycol 4000
(Japanese Pharmacopoeia).
The organic acid suitable for the above sodium salt and potassium salt
thereof includes acetic acid, lactic acid, citric acid, succinic acid,
malic acid, tartaric acid, etc. but the present invention is not limited
thereto. Among these organic acids, citric acid is most preferable.
Preferred formulation of the bowel lavage composition of the present
invention using preferred components is a follows:
______________________________________
Polyethylene glycol 4000
50-120 g
Sodium citrate 20-60 mmol
Sodium chloride 20-50 mmol
Potassium chloride 4-12 mmol
Sodium sulfate 0-20 mmol
______________________________________
The bowel lavage composition of the present invention can be prepared in
the following manner. Firstly, each component is pulverized into fine
powder with a pulverizer and then sieved. Then, each component of the
above formulation is uniformly mixed with each other using a mixer and
then divided into a suitable unit composition with a dividing machine,
such as for 1 liter, 2 liter, 3 liter or 4 liter lavage solution.
The lavage solution of the present invention can be prepared in accordance
with a usual procedure of preparing transfusions. The concentration of the
intestinal washing solution can optionally be selected ranging from about
4 times higher concentration than that of an isotonic solution to a nearly
isotonic concentration (osmotic pressure, around 290 mOsm/liter) in
accordance with the dilution ratio when used.
The bowel lavage composition of the present invention may also contain
sweetening, spice and the like if necessary.
The bowel lavage composition of the present invention allows for easy
preparation of the lavage solution when used. The lavage solution of the
present invention is easily taken by patients, has reduced absorption of
water, does not exert influence upon the electrolyte balance in the living
body and shows an excellent cleansing effect. Further, the lavage solution
of the present invention does not contain hydrogen carbonate ion, and
hence, is pharmaceutically stable and can be stored for a long period of
time, which saves time for preparation when used.
The present invention is illustrated by the following Examples and
Experiments, but should not be construed to be limited thereto.
EXAMPLE 1
Sodium chloride (Japanese Pharmacopoeia), potassium chloride (Japanese
Pharmacopoeia) and sodium citrate (Japanese Pharmacopoeia) were sieved
with a sieve of 500 .mu.m screen diameter. Sodium chloride (35.0 kg),
potassium chloride (22.4 kg) and sodium citrate (309 kg), sieved as
mentioned above, were put in a VI-500 Mixer (manufactured by Tokuju
Kosakusho K.K.) and the mixture was blended for 20 minutes to prepare
mixed electrolyte powder. Paraffin-like polyethylene glycol 4000 (Japanese
Pharmacopoeia) was pulverized with a Pinmil Pulverizer (manufactured by
Nara Kikai K.K.) and then sieved with a sieve of 500 .mu.m screen diameter
to prepare pulverized polyethylene glycol 4000.
The above pulverized polyethylene glycol 4000 (225 kg) and the above mixed
electrolyte powder (36.6 kg) were put in a VI-500 Mixer and the mixture
was blended for 20 minutes to give a uniform mixture. The resulting mixed
powder was filled in an aluminum bag made of polyester, polyethylene and
aluminum foil using an automatic quantitative bag-filling machine FA-400
(manufactured by Yamato Seiko K.K.) to give 1200 bags of bowel lavage
composition (for 2 liter) with each bag containing 174.4 g of the
composition. The content of the composition in each bag can be varied if
necessary.
EXAMPLE 2
The mixed electrolyte powder (36.6 kg) prepared as in Example 1 and
polydextrose (225 kg) were put in VI-500 Mixer and the mixture was blended
for 30 minutes to give a uniform mixed powder. Using this mixed powder
(210 kg), the procedure of Example 1 was repeated to give 1200 bags of the
bowel lavage composition containing each 174.4 g of the mixed powder.
EXAMPLES 3 TO 11
The procedure of Example 1 was repeated to give the bowel lavage
compositions (for 2 liter) having the formulation as shown in Table 1.
TABLE 1
__________________________________________________________________________
Component
Example No.
(g) 3 4 5 6 7 8 9 10 11
__________________________________________________________________________
Polyethylene
220 180 180 170 140 120 0 0 140
glycol 4000
Dextran 40
0 0 0 0 0 0 440 440 0
Hydroxyethyl-
0 0 0 0 0 0 0 0 0
ated starch
Sodium 5.88
11.8
11.8
14.7
17.6
20.6
20.6
20.6
11.8
citrate
Sodium 2.34
2.92
3.50
3.50
4.09
4.67
2.34
2.34
2.92
chloride
Potassium
1.49
1.49
1.49
1.49
1.49
1.49
1.49
1.49
1.49
chloride
Sodium 0 0 0 0 0 0 0 0 5.68
sulfate
__________________________________________________________________________
EXAMPLE 12
A 100 liter dissolving vessel equipped with a stirrer was charged with
polyethylene glycol 4000 (7500 g), sodium chloride (117 g), potassium
chloride (74.6 g) and sodium citrate (Japanese Pharmacopoeia; 1030 g) and
thereto was added distilled water while stirring to dissolve the mixture
so that the total amount of the mixture became 100 liters. Each 2 liters
of this solution was poured into vessels made of a synthetic resin to give
50 lavage solutions (for 2 liter).
In accordance with the above procedure, the conventional lavage solutions
BES, Golytely and physiological saline were prepared for use in the
following Experiments. Table 2 shows the components (g) contained in each
2 liter of the lavage solutions.
TABLE 2
______________________________________
BES Golytely PS*
______________________________________
Polyethylene glycol 4000
0 118 0
Sodium hydrogencarbonate
5.04 3.37 0
Sodium chloride 12.9 2.93 18.0
Potassium chloride
1.49 1.49 0
Sodium sulfate 0 11.4 0
______________________________________
(Note) PS: Physiological saline
Experiment 1 (Cleansing effect)
The lavage compositions (for 2 liter) prepared in Examples 1, 2, 3, 4, 8,
10 and 11 were dissolved in distilled water to give the lavage solutions
having the total amount of 2 liters. These lavage solutions and Golytely
were tested for their cleansing effect in rats.
Male SD rats 8 to 10 weeks old, which have been fasted for 24 hours, were
divided into 5 animals in each group. Each 20 ml/kg of the lavage
solutions of the present invention and Golytely were orally administered
to the animals for 15 times with 10 minutes interval. Ten minutes after
the last administration, whole intestinal contents from pyloric orifice to
rectum were obtained and the dry weight thereof was measured. The results
are shown in Table 3.
It was found that both the lavage solutions of the present invention and
Golytely showed good cleansing effect.
TABLE 3
______________________________________
Dry weight (mg)
Cleansing degree (%)
______________________________________
Control 350 .+-. 41 --
Ex. 1 111 .+-. 13 68.3
Ex. 2 177 .+-. 20 49.4
Ex. 3 177 .+-. 49 49.4
Ex. 4 108 .+-. 19 69.1
Ex. 8 127 .+-. 20 63.7
Ex. 10 149 .+-. 23 57.4
Ex. 11 125 .+-. 15 64.3
Golytely 137 .+-. 30 60.9
______________________________________
Experiment 2 (Effect on the intestinal electrolyte balance)
The lavage compositions (for 2 liter) prepared in Examples 1, 3, 4, 5, 6,
7, 8 and 11 were dissolved in distilled water to give the lavage solutions
having the total amount of 2 liters. These lavage solutions and the above
three kinds of solutions prepared in Example 12 (BES, Golytely and
physiological saline) were tested for their effect on the intestinal
electrolyte balance.
The test animals and the administration route were the same as those in
Experiment 1. Ten minutes after the last administration, the intestinal
contents in the colon were obtained and centrifuged. The supernatant was
analyzed for the electrolyte concentration with a sodium-potassium
automatic analyzer NOVA 1 (manufactured by Nova Biomedical) and a chloride
counter CL-6MP (manufactured by Hiranuma). The results are shown in Table
4. It was found that the bowel lavage compositions of the present
invention, BES and Golytely exerted substantially no influence upon the
intestinal electrolyte balance.
TABLE 4
______________________________________
Changes in intestinal electrolyte level (mM)
Na.sup.+ K.sup.+ Cl.sup.+
______________________________________
Ex. 1 -3.8 -1.59 -17
Ex. 3 -9.2 -5.32 -13
Ex. 4 -5.6 -3.49 -19
Ex. 5 -12.4 -4.00 -23
Ex. 6 -7.1 -2.12 -21
Ex. 7 -7.7 -2.12 -26
Ex. 8 -10.6 -1.01 -31
Ex. 11 -11.1 -2.01 -23
BES -15.3 -0.49 -22
Golytely -8.9 -2.12 -28
Physiological
-43.0 +7.97 -40
saline
______________________________________
(Note): The symbols + and - show an increase and a decrease of the
electrolyte levels from those in the original solutions, respectively.
Experiment 3 (Effect on the serum electrolyte balance)
The lavage compositions (for 2 liter) prepared in Examples 1 to 11 were
dissolved in distilled water to give the lavage solutions having the total
amount of 2 liters. These lavage solutions and the above three kinds of
the solutions prepared in Example 12 (BES, Golytely and physiological
saline) were tested for their effect on the serum electrolyte balance.
The test animals and the administration route were the same as those in
Experiment 1. Ten minutes after the last administration, the animals were
anesthetized with ether and blood was obtained from the abdominal aorta to
measure the serum electrolyte level. The pH value and the hematocrit value
which can be used as an index of waterabsorption were also measured. Table
5 shows the results of both serum electrolyte level and hematocrit value.
As clearly shown in Table 5, the lavage solutions of the present invention,
BES, Golytely and physiological saline exerted substantially no influence
upon serum electrolyte level, blood pH and hematocrit value.
TABLE 5
__________________________________________________________________________
Serum electrolyte level (mEq/liter)
Hematocrit
Na.sup.+
K.sup.+
Cl.sup.-
HCO.sub.3.sup.-
pH value (%)
__________________________________________________________________________
Control
148.8 .+-. 0.7
4.98 .+-. 0.12
108 .+-. 0
23.0 .+-. 0.4
7.43
42.3 .+-. 0.4
Ex. 1 148.1 .+-. 1.3
5.11 .+-. 0.18
106 .+-. 1
28.6 .+-. 0.9
7.48
42.0 .+-. 0.7
Ex. 2 148.7 .+-. 0.5
4.87 .+-. 0.15
110 .+-. 1
25.6 .+-. 0.9
7.46
42.6 .+-. 0.8
Ex. 3 148.0 .+-. 1.2
5.05 .+-. 0.07
108 .+-. 1
25.7 .+-. 0.8
7.44
43.3 .+-. 0.7
Ex. 4 147.3 .+-. 0.5
4.94 .+-. 0.13
109 .+-. 1
24.9 .+-. 0.6
7.51
40.1 .+-. 0.4
Ex. 5 147.2 .+-. 0.6
5.01 .+-. 0.08
108 .+-. 0
26.9 .+-. 0.3
7.49
40.8 .+-. 0.3
Ex. 6 146.4 .+-. 1.1
5.07 .+-. 0.14
106 .+-. 1
24.7 .+-. 1.1
7.41
41.5 .+-. 1.0
Ex. 7 149.5 .+-. 0.5
4.80 .+-. 0.11
109 .+-. 1
25.7 .+-. 0.5
7.49
41.6 .+-. 0.9
Ex. 8 148.9 .+-. 1.3
4.98 .+-. 0.08
109 .+-. 1
26.6 .+-. 0.8
7.46
40.4 .+-. 0.7
Ex. 9 149.2 .+-. 0.5
5.12 .+-. 0.10
107 .+-. 1
25.1 .+-. 0.6
7.46
41.9 .+-. 0.2
Ex. 10 149.5 .+-. 0.6
5.08 .+-. 0.11
107 .+-. 1
26.0 .+-. 0.8
7.41
42.2 .+-. 0.1
Ex. 11 149.9 .+-. 0.5
4.50 .+-. 0.19
108 .+-. 1
26.6 .+-. 0.4
7.50
40.8 .+-. 0.6
BES 152.1 .+-. 0.3
4.24 .+-. 0.15
111 .+-. 1
26.6 .+-. 0.5
7.45
40.5 .+-. 0.2
Golytely
148.1 .+-. 1.0
4.64 .+-. 0.08
108 .+-. 1
25.5 .+-. 0.6
7.49
39.5 .+-. 0.7
Physiological
149.5 .+-. 0.7
4.62 .+-. 0.16
119 .+-. 1
17.7 .+-. 1.0
7.30
40.8 .+-. 1.2
saline
__________________________________________________________________________
Experiment 4
Fifteen healthy men and women aging from 22 to 38 years old drank each 100
ml of the lavage solutions of the present invention prepared in Examples
1, 2, 6, and 11, and Golytely for evaluating the taste thereof.
The evaluation was made by the following questionnaire of four ranks:
(A) Very tasty
(B) Rather tasty
(C) Drinkable with patience
(D) Unsavory and undrinkable
The results are shown in Table 6. It was found that the lavage solutions of
the present invention had an improved taste and were much more tasty than
Golytely.
TABLE 6
______________________________________
(Scord No.)
Example No.
1 2 6 11 Golytely
______________________________________
A 0 1 0 0 0
B 15 14 13 11 1
C 0 0 2 4 9
D 0 0 0 0 5
Total 15 15 15 15 15
______________________________________
Top